Guided-mode resonance sensors employing angular, spectral, modal, and polarization diversity for high-precision sensing in compact formats

ABSTRACT

A guided mode resonance (GMR) sensor assembly and system are provided. The GMR sensor includes a waveguide structure configured for operation at or near one or more leaky modes, a receiver for input light from a source of light onto the waveguide structure to cause one or more leaky TE and TM resonant modes and a detector for changes in one or more of the phase, waveshape and/or magnitude of each of a TE resonance and a TM resonance to permit distinguishing between first and second physical states of said waveguide structure or its immediate environment.

PRIORITY

This application claims priority to, and is a divisional of, U.S. patentapplication Ser. No. 11/656,612, filed Jan. 22, 2007, being issued asU.S. Pat. No. 8,111,401, issue date of Feb. 7, 2012, the entire text ofwhich is specifically incorporated by reference herein withoutdisclaimer, and also claims priority to, and is a continuation-in-partof application Ser. No. 12/115,484 filed May 5, 2008, which was adivision of application Ser. No. 11/305,065, filed Dec. 16, 2005, nowU.S. Pat. No. 7,400,399 B2, issued Jul. 15, 2008, the entire text ofwhich is specifically incorporated by reference herein withoutdisclaimer, which was a division of application Ser. No. 09/707,435,filed on Nov. 6, 2000, now U.S. Pat. No. 7,167,615, issued Jan. 23,2007, which claimed priority from provisional patent application Ser.Nos. 60/163,705 filed on Nov. 5, 1999 and 60/164,089, filed on Nov. 6,1999,the entire text of which is specifically incorporated by referenceherein without disclaimer

BACKGROUND OF THE DISCLOSURE

Field of the Invention

The present disclosure provides optical sensors operating with resonantleaky modes in periodic structures where angular, spectral, modal, andpolarization diversity is advantageously applied for high-precisionsensing in compact systems formats. Cross-referenced data sets thusobtained, fitted to numerical models, provide added degrees of precisionand accuracy to enhance the quality of the sensing operation in a broadvariety of applications.

Description of the Related Art

Numerous optical sensors for bio- and chemical detection have beendeveloped commercially and in the research literature. Example devicesinclude the surface plasmon resonance sensor, MEMS based cantileversensors, resonant mirror, Bragg grating sensors, waveguide sensors,waveguide interferometric sensors, ellipsometry and grating coupledsensors. Of these, although dramatically different in concept, function,and capability, the surface plasmon resonance (SPR) sensor comes closestto the guided-mode resonance (GMR) sensor that is the subject of thisdisclosure. Both GMR and SPR sensors provide tag-free biochemicaldetection capability.

The term surface plasmon (SP) refers to an electromagnetic field inducedcharge-density oscillation that can occur at the interface between aconductor and a dielectric (for example, gold/glass interface). An SPmode can be resonantly excited by parallel-polarized TM polarized light(TM polarization refers to light with the electric field vector in theplane of incidence) but not with TE polarized light (the TE polarizationrefers to light where the TE vector is normal to the plane ofincidence). Phase matching occurs by employing a metallized diffractiongrating, or by using total internal reflection from a high-indexmaterial, such as in prism coupling, or an evanescent field from aguided wave. When an SPR surface wave is excited, an absorption minimumoccurs in a specific wavelength band. While angular and spectralsensitivity is very high for these sensors, the resolution is limited bya broad resonant linewidth (˜50 nm) and signal to noise ratio of thesensor response. Furthermore, as the operational dynamic range of thesensor is increased, the sensor sensitivity typically decreases. Sinceonly a single polarization (TM) can physically be used for detection,change in refractive index and thickness cannot simultaneously beresolved in one measurement. This is particularly important in chemicalsensor applications where binding kinetics include thickness changes atthe sensor surface, while background refractive index can vary dependingon analyte concentration. The disclosure provided herein can remedy someof the limitations of the present art.

Magnusson et al. discovered guided-mode resonance filters that weretunable on variation in resonance structure parameters. Thus, spectralor angular variations induced via layer thickness change or on change inrefractive index in surrounding media or in device layers can be used tosense these changes. Wawro et al. discovered new GMR sensor embodimentsas well as new possibilities of applications of these when integratedwith optical fibers. There are also additional aspects of GMR sensors invarious application scenarios.

SUMMARY OF THE DISCLOSURE

The present disclosure provides tag-free resonant sensors operating inreflection (that is, bandstop filter) or in transmission (that is,bandpass filter) wherein shaped angular spectra illuminate the GMRsensor element. These spectra simultaneously cover the incident angularranges of interest with the received signal illuminating a lineardetector array, or a CCD matrix, or other detectors, directly. Onbiomolecular attachment, or upon other variations of interest in thesensing region, these relatively narrow reflected or transmitted angularspectra alter their location on the detector matrix yielding aquantitative measurement of the molecular event of interest. Moreover,as the resonances arise as distinct TE and TM polarized responses,switching the input light polarization state can be applied to improvethe quality of the sensing operation, or to measure additionalparameters, by obtaining dual TE/TM resonance data. In addition, ifdesired, the input light can be spectrally tuned through a set ofdiscrete wavelengths, thereby spatially shifting the locations of themeasured spectra on the detectors providing possibilities of addedenhancements of the precision of the measurement. Finally, sensoroperation with multiple resonance peaks due to presence of multipleleaky waveguide modes can even further add to the measurement precision.

These operational modalities (angular, spectral, modal, andpolarization) can be used in various combinations as needed. The sensorscan be arranged into compact, high-density platforms requiring minimalreagent volumes. Therefore, as explained in this disclosure, thisapproach has numerous advantageous uses in practical sensor systems forhigh-precision measurement applications.

BRIEF DESCRIPTION OF THE FIGURES

To aid in the understanding of uses and implementations of the presentdisclosure for those having skill in the art, reference is made tonumerous figures enclosed herein for clarity and expediency.

FIG. 1 shows an example of a biomolecular binding event on a surface ofa biosensor.

FIG. 2 provides a schematic illustration of example bacterial detection.

FIG. 3 gives explanation of diffraction by resonant photonic-crystalwaveguide structures with the zero-order condition and leaky moderesonance excitation clearly defined.

FIG. 4 provides a comparison between experiment and theory for adielectric resonance element.

FIG. 5 shows the electric-field profile of the leaky mode at resonancefor the element in FIG. 4.

FIG. 6 shows a computed instantaneous “snapshot” of the electromagneticstanding-wave pattern associated with the leaky mode in FIG. 5 at amaxima.

FIG. 7 illustrates a guided-mode resonance refractive index sensoremploying TE and TM polarization diversity and depicts the structureproducing the computed response.

FIG. 8 shows corresponding TE-polarization resonance wavelength shiftfor large dynamic range sensing for the example in FIG. 7.

FIG. 9 illustrates thickness sensing in air.

FIG. 10 provides measured GMR sensor spectral response in air for aTE-polarized (top, left) device surface modified with silane chemicallinker (bottom, left). A scanning electron micrograph (SEM) is alsoshown (top, right) as well as a device model (bottom, left).

FIG. 11 depicts a submicron grating contact printing technique and anelectron microscope picture of a 520-nm period grating contact printedin an optical adhesive medium.

FIG. 12 shows calculated TE-polarization angular response of a GMRsensor for differing added thickness (d_(bio)) of biomaterials whileFIG. 13 shows the corresponding TM-polarization response.

FIG. 14 is a schematic drawing of a proposed resonant sensor system withdual polarization detection. The diverging beam from a source such as anLED or LD or VCSEL is incident on the sensor at various anglessimultaneously.

FIG. 15 gives an example GMR sensor embodiment with diverging input beamand associated detector employing polarization-diverse detection.

FIG. 16 is a schematic drawing of an arbitrarily-sized N×M array ofmicrowells integrated with a GMR-sensor/detector unit as detailed inFIG. 15.

FIG. 17 explains polarized sensing in transmission mode where the TEpeak (or minimum) and the TM peak (or minimum) are directed to thedetector array aided by a reflection at a microwell wall.

FIG. 18 is an illustration of the experimental use of GMR sensorpolarization diversity to quantify biotin binding to a silane-coatedsensor surface. The molecular attachment event is monitored as functionof time. Results for both TE and TM polarizations are shown.

FIG. 19 shows an example element structure that achieves bandpass filtercharacteristics and thus realizes a GMR sensor operating intransmission. This element can be realized in the silicon-on-insulator(SOI) materials system.

FIG. 20 provides computed transmission-type SOI resonant sensor spectrafor different added biomaterial thicknesses. The sensor operates in airwith the incident, reflected (R), and transmitted (T) waves as shown inFIG. 19. The incident wave is TM polarized in this example. The sensordesign is shown in FIG. 19.

FIG. 21 depicts a sensor/detector configuration associated with sensingoperation in direct transmission.

FIG. 22 gives calculated TE angular responses associated with a GMRsensor layout such as the one shown in FIG. 21 for different addedthickness of biomaterials.

FIG. 23 shows calculated TE angular responses for the GMR sensorconfiguration in FIG. 21 for varying input wavelength to illustratewavelength diversity. In this computation, d_(bio)=100 nm. The diverginginput beam covers the angular range of interest automatically.

FIG. 24 gives calculated TM angular response of the GMR bandpass-typesensor shown schematically in FIG. 19 for differing biolayer thickness.The diverging input beam covers the angular range of interestautomatically. Parameters are as in FIG. 19 and the input wavelength isset to λ=1.5436 μm in this example.

FIG. 25 shows a sensor/detector configuration associated with sensingoperation in compact layout with direct, polarization-enhanceddetection. The locations of TE and TM resonance nulls (or peaks) on thedetector array are schematically indicated by the dashed arrows.

FIG. 26 illustrates a sensor/detector configuration associated with asensing operation in direct transmission across a flow channel in amicrofluidic bio- or chemical sensing system.

FIG. 27 shows an HTS platform with a single-source plane-wave input andwavefront shaping with a lens-array to implement angularly-addressableGMR sensor array without moving parts.

FIG. 28 is of an HTS platform with a single-source input and wavefrontshaping with a lens-array to implement angularly addressable GMR sensorarray in a microfluidic context.

FIG. 29 indicates a GMR sensor array fabricated in plastic or glassmedia by imprinting and molding methods.

FIG. 30 is of a GMR sensor array fabricated in the silicon-on-insulatormaterials system.

FIG. 31 provides calculated TE-reflectance angular response of a GMRmultimode sensor for differing added thickness (d_(bio)) ofbiomaterials.

FIG. 32 provides calculated angular transmittance spectrum correspondingto the multimode sensor of FIG. 31.

FIG. 33 shows a computed transmittance spectrum corresponding to thedevice parameters in FIG. 31 at normal incidence θ=0 exhibitingmultimode resonance characteristics. This multimode biosensor operateswith leaky modes TE₀, TE₁, and TE₂ in the wavelength range depicted. Thehighest sensitivity is provided by the TE₂ mode in this exemplary case.

FIG. 34 depicts a single source system utilizing an optical splitter andoptical fiber delivery.

FIG. 35 depicts a single channel schematic illustration of a label-freeguided-mode resonance sensor system for detecting chemical or biologicalanalyte bonded to an antibody.

FIG. 36 depicts a reflection configuration utilizing an optical fiberarray for light delivery.

FIG. 37 depicts a reflection sensor system employing a scanning linesource.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENT

Background

It has been suggested by the inventors that by changing the refractiveindex and/or thickness of a resonant waveguide grating, its resonancefrequency can be changed, or tuned. The present inventors havediscovered that this idea has applications for biosensors as the buildupof the attaching biolayer can be monitored in real time, without use ofchemical tags, by following the corresponding resonance wavelength shiftwith a spectrometer. Thus, the association rate between the analyte andits designated receptor can be quantified; in fact, the characteristicsof the entire binding cycle, involving association, disassociation, andregeneration can be registered. Similarly, small variations in therefractive indices of the surrounding media, or in any of thewaveguide-grating layers, can be measured. A new class of highlysensitive bio- and chemical sensors has thus been enabled. This sensortechnology is broadly applicable to medical diagnostics, drugdevelopment, industrial process control, genomics, environmentalmonitoring, and homeland security.

To address one exemplary use in some detail, high performance, tag-freephotonic-crystal GMR sensors are attractive for improved process controlin drug development applications. This method is particularly usefulowing to the enhancement in detection accuracy this sensor technologycan provide to advance the process of drug development and screening. Inthis industry, millions of distinct chemical compounds need to berapidly and accurately screened to determine which compounds bind to aparticular protein or inhibit a target reaction. A purpose of highthroughput screening (HTS) is to eliminate unpromising compounds beforefurther development costs are incurred. Current HTS technologiestypically use fluorescence or radioactive chemical tags as indicators ofbioactivity. Due to the indicator-compound binding complexity, sometimesentirely new assays must be carefully designed utilizing new indicatortechnologies or reaction chemistries. There is increasing demand fornovel sensor techniques that do not require labeling, and allow a widerange of materials to be selectively screened in real-time with minimalassay development (using readily available antibody-antigen, nucleicacids and other highly selective biomaterials). The capability to reduceerrors from screening variables (such as temperature, and backgroundfluid variations), as well as the ability to monitor binding dynamics inreal time with simple array configurations are other desired features.High-precision GMR sensor methods, such as those disclosed here, canmeet these needs for high throughput screening applications.

The sensor includes a periodic dielectric waveguide (also referred to asphotonic crystal) in which resonant leaky modes are excited by anincident optical wave. Incident broadband light is efficiently reflectedin a narrow spectral band whose central wavelength is highly sensitiveto chemical reactions occurring at the surface of the sensor element.Interaction of a target analyte with a biochemical layer on the sensorsurface yields measurable spectral shifts that directly identify thebinding event without additional processing or foreign tags. Abio-selective layer (such as antibodies) can be incorporated on thesensor surface to impart specificity during operation as illustrated inFIG. 1. Sensor designs with sensitivities to thickness changes from thenanoscale (<0.1 angstroms) to as large as several microns have beenanalyzed. Thus, the same sensor technology can be used to detect bindingevents for small molecule drugs (<1 nm) and proteins (<10 nm), as wellas larger bacterial analytes (>1 μm) as depicted schematically in FIG.2. High resolution (obtained via narrow, well defined resonance peaks)and high sensitivities (associated with surface-localized leaky modes)provide a high probability of accurately detecting an event.Additionally, both major polarization states have independent resonantpeaks to accurately sense a biomaterial binding event. This featureenables the capability to distinguish between average thickness changesand average density changes occurring at the sensor surface. Thus thesensor resonance response to a targeted chemical binding event (whichincludes a molecular conformational change) is distinguishable fromunbound material settling on the sensor surface, thereby decreasing theoccurrence of false positive readings.

GMR sensor technology is particularly versatile. The biomolecularreaction associated with an individual sensor, or sensor element in anarray, can be simultaneously measured using the various properties oflight including angular spectrum, wavelength spectrum, and polarization.Moreover, the GMR element itself can be designed to exhibit distinctlypolarized resonances in a single peak due to a single leaky mode, saythe TE₀ fundamental mode, or in multiple peaks originating in multipleleaky modes, for example, the TE₀, TE₁, and TE₂ modes. Such multiplemodes will be made excitable, by proper sensor design, within theangular and wavelength spectral regions of interest. The electromagneticfield structure of the resonant mode can be configured such that thesensor operates with an evanescent tail in the sensing region or,alternatively, as a bulk mode sensor in which the leaky mode fullyencloses the sensing region. Indeed, a particular operational leaky modecan be selected to maximize the light-measurand interaction to raise thedetection sensitivity. For example, in a particular design, operation inthe TE₂ mode may yield superior results over the TE₀ mode. The detectionschemes thus summarized increase the amount and reliability of theinformation collected about the molecular event over those gathered byother means.

This sensor concept is broadly applicable in terms of materials,operating wavelengths, and design configurations. It is multifunctionalas only the sensitizing surface layer needs to be chemically altered todetect different species. Operation in both air and liquid environmentsis possible. Due to the flexibility in materials selection,environmentally friendly dielectrics can be chosen in the fabrication ofthe sensor elements. Applicable materials include polymers,semiconductors, glasses, metals, and dielectrics.

Guided-Mode Resonance Effect

FIG. 3 shows the interaction of a thin-film waveguide grating (photoniccrystal slab) and an incident plane wave. As the period Λ is reduced,higher-order propagating waves become increasingly cut off until thezero-order regime in FIG. 3(b) obtains. If the structure contains anappropriate waveguide, the first-order waves, now evanescent or cut off,can induce a resonance by coupling to a leaky mode. Indeed, thezero-order regime is often preferred as no energy is wasted inpropagating higher-order diffracted waves such as those in FIG. 3(a).

Such thin-film structures containing waveguide layers and periodicelements (photonic crystals), under the correct conditions, exhibit theguided-mode resonance (GMR) effect. When an incident wave isphase-matched, by the periodic element, to a leaky waveguide mode shownin FIG. 3(c), it is reradiated in the specular-reflection direction withreflectance R as indicated in FIG. 3(c) as it propagates along thewaveguide and constructively interferes with the directly reflectedwave. Conversely and equivalently, the phase of the reradiated leakymode in the forward, directly transmitted wave (transmittance T)direction in FIG. 3(c) is π radians out of phase with the directunguided T wave, thereby extinguishing the transmitted light.

Experimental Bandstop Filter Example

FIG. 4 shows the measured and calculated spectral reflectance of adielectric guided-mode resonance device. This device acts as a bandstopfilter with the spectrum of interest reflected in a narrow band withrelatively low sidebands. Although the theoretical calculation predicts100% peak efficiency for a plane wave incidence, it is diminished inpractice by various factors such as material and scattering losses,incident beam divergence, and the lateral device size; here theexperimental peak is at 90% efficiency. This resonant element wasfabricated by depositing an HfO₂ layer (˜210 nm) and a SiO₂ layer (˜135nm) on a fused silica substrate (1-inch diameter). The SiO₂ grating wasobtained by a series of processes including holographic recording of aphotoresist mask grating (period of λ=446 nm) with an Ar+ UV laser(λ=364 nm) in a Lloyd mirror interference setup, development, depositionof ˜10 nm Cr mask layer on top of the photoresist grating, lift-off ofthe photoresist grating, and subsequent reactive-ion etching of the SiO₂layer with CF₄. The surface roughness evident in the SEM contributes tothe reduction in peak efficiency.

Leaky-Mode Field Structure

In addition to the reflection/transmission properties of propagatingelectromagnetic waves, the near-field characteristics of resonantperiodic lattices, including localization and field-strengthenhancement, are of interest in sensor applications. The computed nearfield pattern associated with the fabricated example structure of FIG. 4is presented in FIG. 5. Numerical results are obtained with rigorouscoupled-wave analysis (RCWA) to provide quantitative information onrelative field strengths and spatial extents associated with the nearfields. As shown in FIG. 5, the zero-order S₀ wave (S₀ denotes theelectric field of the zero order) propagates with reflected waveamplitude close to unity producing the standing-wave pattern shown byinterference with the unit-amplitude input wave. Thus, at resonance,most of the energy is reflected back. Simultaneously, the first-orderevanescent diffracted waves denoted S₁ and S⁻¹ constitute thecounter-propagating leaky modes in this example. In this particularsensor, the maximum field value is located in the homogeneous layer withthe evanescent tails gradually penetrating into the substrate and coveras clearly displayed in FIG. 5. FIG. 6 shows the standing wave patternformed by the counter-propagating S⁻¹ and S₊₁ waves at a certain instantof time. Since the S_(±1) space harmonics correspond to localized waves,they can be very strong at resonance. Depending on the level of gratingmodulation (Δ∈=n_(H) ²−n_(L) ²), the field amplitude can range from˜×10×1000 in the layer relative to the input wave amplitude whichrepresents a large increase in local intensity I˜S². The maximumamplitude of S₁ is approximately inversely proportional to modulationstrength. The maximum amplitude of S₁ is approximately inverselyproportional to modulation strength. In general, small modulationimplies narrow linewidth Δλ and a large resonator Q factor Q=λ/Δλ.

Exemplary Sensor Response and Sensitivity

The computed spectral response for a single-layer sensor designed foruse in a liquid environment is provided in FIG. 7. This sensor can befabricated with Si₃N₄ and patterned by plasma etching to create thediffractive layer. One-dimensional resonant waveguide grating structureshave separate reflectance peaks for TE (electric vector normal to thepage) and TM polarized incident waves. The calculation shows that thisdesign can resolve an average refractive index change of 3×10⁻⁵refractive index units (RIU) assuming a spectrometer resolution of 0.01nm. A nearly linear wavelength shift is maintained (FIG. 8) for a widerefractive index change of the medium in contact with the gratingstructure (n_(c)=n_(L)=1.3 to 1.8), making this a versatile sensor witha large dynamic range. The sensitivity of a biosensor is defined as themeasured response (such as peak wavelength shift) for a particularamount of material that is detected. This indicates the maximumachievable sensitivity to the analyte under detection. Sensor resolutionincludes realistic component limitations such as spectroscopic equipmentresolution, power meter accuracy, bioselective agent response, and peakshape or linewidth. Linewidth is the full width at half maximum (FWHM)of the reflected peak response. It affects the accuracy of spectroscopicsensors as a narrow line typically permits improved resolution ofwavelength shifts; resonant waveguide grating sensors typically havenarrow linewidths on the order of ˜1 nm controllable by design. Whileresonant sensors can monitor tiny refractive index changes, they canalso be used to detect thickness changes at the sensor surface, as thecomputed results in FIG. 9 show for realistic materials and wavelengths.

Exemplary Sensor Results

As exemplified in FIG. 10, the use of GMR sensor technology forbiosensing applications has been investigated with protein bindingstudies in air utilizing a 2-layer resonant element illuminated atnormal incidence. In this case, the clean grating surface is firstchemically modified with amine groups by treating with a 3% solution ofaminopropyltrimethoxysilane (Sigma) in methanol (FIG. 10 top, left). Thedevice is then washed in a solution of bovine serum albumin (BSA, 100mg/ml, Sigma) and a deposited 38 nm thick layer of BSA results in areflected resonant peak spectral shift of 6.4 nm (FIG. 10 bottom, left).It is noted that minimal signal degradation results from the biomateriallayer on the sensor surface with reflectance remaining at ˜90% beforeand after BSA attachment.

Fabrication of Resonant Sensor Elements by Contact Printing

In addition to the methods described thus far, economic contact printingmethods are attractive to imprint optical polymers with desiredsubmicron grating patterns. A silicone grating stamp can be used toimprint the grating into a thin layer of UV curable optical adhesive(FIG. 11 (a)). A waveguide layer is then deposited on the top surface ofthe grating by sputtering with a thin layer of Si₃N₄ or other suitablemedia. Alternatively, the grating is coated with a high index spin-onTiO₂ polymer film to yield a high-quality resonant sensor element. Anexample of a contact printed grating is shown in FIG. 11 (b).

Dual-Mode TE/TM Polarized GMR Sensors

Simultaneous detection of the TE and TM resonance shift on biolayerattachment to the sensor can greatly improve the quality of the sensingoperation. This permits accurate determination of the complete biolayerproperties; that is refractive index and thickness. FIGS. 12 and 13 showcomputed results indicating the resonance shifts in angle for bothpolarizations. Indeed, the moderate angular TE/TM resonance separation,realizable with proper element design, enables simultaneous detection ofthe two signals on a linear detector array as indicated in FIG. 14 witha diverging illumination by a light emitting diode (LED, possiblyfiltered for spectral narrowing), or a vertical-cavity surface-emittinglaser (VCSEL), or laser diode (LD) with λ=850 nm that automaticallycovers the angular range of interest. In this example, the interrogatinglight beam enters through a cover medium such as a fused silica orplastic sheet (refractive index n_(c)). The light distributions ofinterest appear as reflection peaks on the detector. This exampleillustrates use of a high-index polymer material serving as both thehomogeneous layer and the periodic layer. This could be fabricated, forexample, by using a silicone mold for grating formation in commercialTiO₂-rich, thermally, or UV, curable polymer medium that is spin coatedon the support wafer. Alternatively, a high-index waveguide layer can bedeposited on a support wafer and the periodic layer molded on top of it.

FIG. 15 illustrates an application of one embodiment of the presentinvention in a biomolecular sensing context. While unpolarized lightwill provide TE and TM resonance peaks on the detector array or matrix,the signal-to-noise (S/N) ratio can be improved by switching between thepolarization states as indicated in FIG. 15 and scanning the detectorfor separate TE and TM signals temporally synchronized with thepolarization switch. Moreover, to further enhance the S/N ratio, thelight source can be equipped with a beam shaping element to sculpt thelight distribution on the sensor in an optimal manner. In fact, in someapplications, the use of a converging rather than diverging wavefrontmay be desired. Such beam shaping can, for example, be performed withappropriate holographic or diffractive optical elements. This allowswavefronts of arbitrary amplitude and phase distribution to begenerated. FIG. 16 indicates use of the device in FIG. 15 in amulti-well system. In the pharmaceutical industry, microwell plates areused for effective drug compound screening in which this systemapplication might find advantageous deployment. FIG. 17 illustrates anadditional configuration where now the detector matrix is on top of thewell and the transmitted nulls (or peaks) associated with TE and TMresonance are measured. As a biolayer adds to the sensor, the locationof the nulls on the detector shifts to permit quantification of thebinding event. In this example, the incident wave is at an angle and thesignal recovery is aided by reflections off the microwell walls.

Preliminary experiments have demonstrated the polarization diversityfeature of this technology, which supplies separate resonance peakshifts for each polarization (TE and TM), providing a means for highdetection accuracy as discussed above. FIG. 18 shows an example resultpertaining to a GMR biosensor application.

Bandpass GMR Sensors

Transmission, or bandpass, resonance sensor elements can be fabricatedin a variety of media including silicon-on-insulator (SOI),silicon-on-sapphire (SOS), and directly imprintable thermally-curable orUV-curable polymers. Formation of the periodic layer can be accomplishedwith traditional methods including e-beam writing and etching,holographic interferometry, and nanoimprint lithography withprefabricated masters. To clarify this embodiment, FIG. 19 shows atransmission sensor designed in an exemplary SOI structure. FIG. 20illustrates the response of the sensor to addition of a biomolecularlayer of thickness d_(bio) to the sensor surface. The transmission peakalters its spectral location in a sensitive manner. This plot should becontrasted, for example, with the sensor in FIGS. 12-14 that operates inreflection. As the biomaterial attaches to the surface of the sensor,the resonance wavelength shifts substantially at a rate of ˜1.6 nmspectral shift per nm added material. Note the particular profile designthat achieves this performance in this case.

Planar Compact GMR Sensors and Arrayed Sensor Systems

For ease of fabrication and to reduce cost, we now discloseimplementation of the embodiments of the present invention presentedabove in planar systems formats. The sensors will operate intransmission. Thus, the light enters the sensor that is in contact witha medium whose interaction with the sensor is of interest. The lighttravels across the medium to the detector on which a transmittedintensity minimum (bandstop filter) or intensity maximum (bandpassfilter) is measured. Spatial shifts in the locations of these lightdistributions permit quantification of key features of the biomolecularbinding reaction.

FIG. 21 illustrates this concept for a single sensor interrogated with adiverging beam from a laser diode (LD), a light-emitting diode (LED), ora vertical-cavity surface-emitting laser (VCSEL). A polarizing,beamshaping, or line-narrowing function can be integrated with thesource as needed. The detector is placed on the opposite side of thesensing volume as shown. FIG. 22 shows the computed intensitydistribution (signal) on the detector matrix for a GMR sensor operatingin bandstop mode thus generating a peak in reflection and a concomitantminimum in transmission. The input wavelength is 850 nm in this example.Two minima appear at symmetric angular locations relative to the sensornormal, since the resonance wavelength at normal incidence differs fromthat for nonnormal incidence. The two simultaneous minima can be used toenhance the accuracy of the sensing operation as two angular shifts areacquired. In FIG. 22, for added biolayer thickness d_(bio)=0 the minimaappear at θ˜6° while for d_(bio)=100 nm the angular resonance is at θ˜5°in this case. FIG. 23 illustrates wavelength diversity; that is, bytuning the input wavelength to a discrete set of wavelengths, additionaldata points can be gathered to improve accuracy in data analysis andfitting to numerical models. As the wavelength changes, so do theresonance angles and the light distributions on the sensors.Additionally, the wavelength controls the location of the minima on thedetector furnishing flexibility in specifying the amount of detectorarea dedicated for each GMR sensor pixel in the sensor array.

As explained in connection with FIG. 20, we have designed many resonantfilters operating with transmitted peaks, that is as bandpass filters.In this case for a design such as that in FIG. 21, there would appearintensity maxima (rather than minima) on the detector array. Suchtransmission elements can be particularly effectively designed inhigh-refractive-index media such as silicon. FIG. 24 illustratesangularly diverse biosensing with a bandpass filter. By setting thewavelength such that the device sustains a transmission peak for theunperturbed surface, an ultra-high sensitivity arrangement is achieved.The most rapid change in the transmitted angular spectra occurs as thedetuning by the biolayer buildup converts the sensor from a bandpass- toa bandstop state at normal incidence as shown in FIG. 24. Thus,sub-nanometer biofilm addition will be directly measurable by a simpleintensity change on the detector on the output side. The shape of theforward transmitted light distribution received by the detector matrixis a sensitive function of the biolayer thickness as FIG. 24 clearlyillustrates.

Yet another polarization diverse embodiment is shown schematically inFIG. 25 in which four simultaneous minima (or peaks) are monitored forhigh-precision biosensing. FIG. 26 provides an embodiment applicable tosensing in microfluidic systems.

In face of the growing number of biological and drug targets, there isan increasing need to invent new ways to profile chemical activity inmassively parallel ways. Simultaneously, there is a need to reduce HTSexpenses by dispensing minimal amounts of reagents for assays. Thus,there are developments in the industry towards nanoliter scale liquiddispensing. The GMR sensor technology disclosed herein is adaptable tomeet these demands. The planar transmission formats indicated andexplained above enable development of multichannel sensor systems.Existing and developing CCD and CMOS detector matrix technology withpixels down to 5-10 μm levels enables precision measurements ofintensity distributions and their variations. Nanoimprint technology andprecision thin-film methods enable fabrication of the requisite GMRsensor arrays. Molding methods are applicable for formatting andimposition of the larger features in these arrays.

FIG. 27 shows a system capable of parallel biosensing in accordance withthe embodiments of the present invention set forth in the presentdisclosure. GMR sensors installed into microwell plates are addressed byangular spectra generated by conversion of an incident plane wave tospherical or cylindrical waves by appropriately-designed array ofdiffractive or refractive microlenses as shown in the figure. Thedetector array mounted above receives the signals to implement precisionbiosensing. FIG. 28 shows a similar operation where the sensors arestimulated by directed flow within flow channels in a microfluidicassembly; FIG. 28 omits the intricate channel construction and detailsassociated with real microfluidic devices.

Practical cost-effective GMR arrays can be fabricated in glass orplastic media. To give an example, diffractive or refractive lens arrayswith given focal lengths and diameters on plastic substrates can bepurchased economically from several vendors. On the blank side of thesubstrate, opposite the lens array, high-index spin-on TiO₂ polymer filmis applied. The grating pattern is then imprinted with a speciallydesigned silicone stamp with appropriate period as noted in FIG. 11,resulting in the GMR sensor. Spill walls to separate different solutionsand to avoid cross-contamination can then be installed by moldingmethods. Alternatively, a high-index thin film is first deposited on thesubstrate with the grating pattern subsequently applied on top. Theresulting GMR array is shown in FIG. 29. FIG. 30 shows a conceptual GMRarray made in SOI to take advantage of existing silicon-basedmicrofabrication methods.

Multimode GMR Sensors

Yet another approach to improve detection reliability is to increase thenumber of operational resonant leaky modes and thereby apply richerspectra for sensing and precision curve fitting. Thus, multipleresonance peaks due to presence of multiple waveguide modes can begenerated and monitored. These multiple modes provide distinct spectralsignatures that may be utilized in precision sensing. FIG. 31 shows theTE-polarization response of a double-layer GMR sensor with parameters asspecified in the figure caption assuming no sidewall attachment. Theseparameters include the following: Calculated TE-reflectance angularresponse of a GMR multimode sensor for differing added thickness(d_(bio)) of biomaterials. Thicknesses d₁=900 nm (homogeneous layer),d₂=270 nm (grating layer); refractive indices n₁=2.00, n_(H)=2.00,n_(L)=1.00, n_(c)=1.46, n_(s)=1.00, n_(bio)=1.40; grating period Λ=450nm; fill factor f=0.5, wavelength of incident light λ=850 nm. With fixedinput wavelength, the reflectance spectrum exhibits several resonancepeaks originating in different leaky modes. On addition of a biolayer,the spectrum responds with measurable change in the angular spectrum asshown in FIG. 31. This spectrum would be monitored in reflection, forexample with the configuration in FIG. 16. FIG. 32 gives thecorresponding transmission spectrum that would be monitored, forexample, in the system of FIG. 27. FIG. 33 illustrates the wavelengthspectrum for this sensor at normal incidence, indicating three leakymodes within the spectral band shown. On account of the particulardistribution of the electromagnetic fields within this sensor, operationin the TE₂ mode gives highest sensitivity, that is, largest angular andspectral shifts per unit added thickness, as demonstrated in FIGS.31-33.

Referring now to FIGS. 34, 35 and 36, and initially to FIG. 34 thereof,a sensor/detector configuration employing fiber coupled light deliveryin a GMR sensor platform is depicted. FIG. 1 shows a single sourcesystem utilizing an optical splitter and optical fiber delivery. Asingle light source is split into “M” channels (with an opticalsplitter) and incident on the sensor array through optical fibers. Thelight exiting from each fiber is shaped by an integrated or externallens/DOE and is incident in free-space on the sensor element.Alternately, the diverging light exiting the optical fiber can beincident on the sensor element directly without the use of beam shapingelements. The optical fiber can be selected based on its numericalaperture or other properties as part of the system design. A polarizingelement or polarization maintaining fiber can be used in the system tocontrol the polarization state(s) incident on the sensor element. Theincident wavelength can be tunable, thus allowing both angular andspectral tuning in a single system.

The system can be configured as a transmission system, where lighttransmitted through the sensor array is detected with a detector matrixon the opposite side of the array from the incident light, as depicted.The system can also be configured as a reflection system, where thelight is incident on the array at an angle and the beam reflected fromthe array is measured with a detector matrix disposed on the same sideof the array as the incident light.

FIG. 35 depicts a single channel schematic illustration of a label-freeguided-mode resonance sensor system for detecting chemical or biologicalanalyte bonded to an antibody. The antibody is depicted as a “Y” and theantibody is depicted as a ball in the cup of the “Y”. The antibodyshould be selected based upon analyte or analytes to be detected. Insome embodiments, bovine, llama or alpaca serum antibody and be used,although the invention is not limited to these antibodies.

In operation, the diverging beam from the fiber coupled laser diode isincident on the sensor with a continuous range of angles. As bindingevents occur at the sensor surface (by the analyte bonding with theantibody), resonance peak changes can be tracked as a function ofincident angle. The resonance occurs at different angles for TE and TMpolarization states of the input light, enabling high-accuracy,cross-referenced detection.

FIG. 36 shows s multiple channel array. It has a reflectionconfiguration utilizing an optical fiber array for light delivery. Theoptical fiber array can also be scanned across a sensor array (foreither reflection or transmission).

For example, to screen a M×N sensor array, an M-fiber array can bescanned across the bottom of N rows of sensor elements. The scanning canoccur by (a) moving the fiber array+detector matrix across the sensorplate, or by (b) moving the sensor plate across the fiber array+detectormatrix.

FIG. 37 depicts a sensor/detector configuration employing a scanningline source. Although FIG. 37 depicts a reflection sensor, however, itcould also be configured as a transmission sensor by positioning thedetector elements on the opposite side of the array plate as theincident light.

The optical source can be a single wavelength (or wavelength selectable)source that is shaped with a line focusing element (for example acylindrical lens). The line focused light illuminates M-sensor elementssimultaneously in the M×N sensor array. The reflected response ismeasured on a M-row of detector matrices (such as a row of CCD detectorelements). The light line source and detector element assembly can bescanned across the bottom of a sensor plate to efficiently read a M×Nsensor array. Note: The line focusing element also acts as the beamshaping element (i.e. can be diverging, converging or any designedwavefront).

The following additional embodiments are also contemplated:

A GMR sensor assembly comprising a waveguide structure configured foroperation at or near one or more leaky modes of input light and adetector for TE and TM resonances having a sensor array with at leastN×M sensor elements.

The GMR sensor assembly defined in paragraph 76 above, furthercomprising a refractive lens to shape the illuminating light.

The GMR sensor assembly defined in paragraph 76 above, furthercomprising an array of refractive lenses to shape the illuminatinglight.

The GMR sensor assembly defined in paragraph 76 above, furthercomprising a diffractive lens to shape the illuminating light.

The GMR sensor assembly defined in paragraph 76 above, furthercomprising means for determining the polarization state and waveshapecharacteristics of a wavefront of input light.

The GMR sensor assembly defined in paragraph 76 above, furthercomprising means for providing input light having at least two differentwavelengths.

The GMR sensor assembly defined in paragraph 76 above, furthercomprising means for providing input light having at least first andsecond polarization characteristics.

The GMR sensor assembly defined in paragraph 76 above, furthercomprising means for detecting at least two resonant modes.

The GMR sensor assembly defined in paragraph 76 above, furthercomprising integrated microfluidic flow channels adjacent said waveguidestructure.

The GMR sensor assembly defined in paragraph 76 above, furthercomprising a substrate, light conditioning elements, and microvialsintegrated into a transparent media.

The GMR sensor assembly defined in paragraph 76 above, wherein the arrayis disposed on an integrated media taken from the group ofsemiconductors, semiconductors/dielectric hybrids,semiconductor/dielectric/metal hybrids, and dielectrics.

The GMR sensor assembly defined in paragraph 76 above, wherein thearrayed sensor elements are physically separate from the illuminatingsource.

The GMR sensor assembly defined in paragraph 76 above, wherein and thearrayed sensor elements are integrated with the source of illuminatinginput light.

The GMR sensor assembly defined in paragraph 76 above, furthercomprising a readout detector in a compact biochip or microbench format.

A guided mode resonant sensor wherein the source of illumination isfiber or waveguide coupled.

A guided mode resonant sensor wherein the waveguide or optical fiber isselected by design to have a specific numerical aperture, polarizationmaintaining property or material specification.

A guided mode resonant sensor wherein the source of illumination isfocused into a line using a line focusing element.

A guided mode resonant sensor wherein the source of illumination isfocused into a line using a line focusing element comprising acylindrical lens.

A guided mode resonant sensor wherein the source of illumination anddetector elements are scanned across the sensor array.

A guided mode resonant sensor wherein a single light source is splitinto several channels using an optical splitter.

A guided mode resonant sensor having an array of opticalfibers/waveguides are used to deliver light to an array of sensorelements.

It will further be understood from the foregoing description thatvarious modifications and changes may be made in the preferredembodiment of the present invention without departing from its truespirit. This description is intended for purposes of illustration onlyand should not be construed in a limiting sense. The scope of thisinvention should be limited only by the language of the followingclaims.

What is claimed is:
 1. A guided-mode resonance sensor assemblycomprising: a waveguide structure including a periodic structure, thewaveguide structure being adapted to receive input light from a sourceof light onto the waveguide structure to cause two or more leaky TEresonant modes and/or two or more leaky TM resonant modes; one or morephotodetectors positioned to receive zero order diffracted light duringnon-control measurement of an analyte having disposed on said waveguidestructure or in its immediate environment for detecting changes in oneor more of the phase, waveshape and/or magnitude of resonances of atleast two different TE guided modes and/or the resonances of at leasttwo different TM guided modes to permit distinguishing between first andsecond physical states of said waveguide structure or in its immediateenvironment.
 2. The guided-mode resonance sensor assembly defined inclaim 1, wherein said guided-mode resonance sensor assembly isconfigured for operation where the input light includes diverging light.3. The guided-mode resonance sensor assembly defined in claim 1, furthercomprising a beam-shaping element for forming an input wavefront ofinput light with known amplitude, and phase characteristics.
 4. Theguided-mode resonance sensor assembly defined in claim 1, wherein thesource of illumination creating said input wavefront of input light isselected from the group of a light emitting diode, laser diode,vertical-cavity surface-emitting laser, and a filtered broadband source.5. The guided-mode resonance sensor assembly defined in claim 1, furthercomprising means for applying a first known polarization state at afirst known time and a second known polarization state at a second knowntime which can be the same as or different from said first known time,and means for analyzing TE and/or TM guided mode resonances respectivelydetected at said first and second known time to permit distinguishingbetween first and second physical states of said waveguide structure orits immediate environment.
 6. The guided-mode resonance sensor assemblydefined in claim 1, further comprising means for selectively inputtingdifferent wavelengths of input light into the waveguide structure. 7.The guided-mode resonance sensor assembly defined in claim 1, whereinthe means for detecting is disposed such that the different TE and/or TMguided mode resonances to be detected are those reflected from thewaveguide structure onto said means for detecting.
 8. The guided-moderesonance sensor assembly defined in claim 1, wherein the means fordetecting is disposed such that the different guided modes of TE and/orTM resonances to be detected are those transmitted through a planethrough the waveguide structure and onto the means for detecting.
 9. Theguided-mode resonance sensor assembly defined in claim 1, wherein themeans for detecting is a matrix of photodetector elements.
 10. Theguided-mode resonance sensor assembly defined in claim 1, wherein thesensor is configured to operate with more than one resonant leaky modes.11. The guided-mode resonance sensor assembly defined in claim 1,further comprising a holographic diffraction element for diffracting theinput light.
 12. The guided-mode resonance sensor assembly defined inclaim 1, wherein the detection means receives the different guided modesof TE and/or TM resonances at an arbitrary angle.
 13. The guided-moderesonance sensor assembly defined in claim 1 wherein the means fordetecting changes in one or more of the phase, waveshape and/ormagnitude of said different TE and/or TM guided mode resonancescomprises sensor array with at least N×M sensor elements.
 14. Theguided-mode resonance sensor assembly defined in claim 13, wherein theinput light has known magnitude and phase characteristics.
 15. Theguided-mode resonance sensor assembly defined in claim 13, wherein theN×M sensor elements configured for illumination by a single light sourceinput through a light shaping port.
 16. A GMR sensor assemblycomprising: a waveguide structure configured for operation at or nearone or more leaky modes of input light, said waveguide structure or itsimmediate environment having physical properties subject to change overtime, a polarization switch in the path of the input light permittingalternate measurements of the spatial positions of TM and TE resonancesat different times a detector for TE and TM resonance positioned toreceive zero order diffracted light during non-control measurement of ananalyte disposed on said waveguide structure or in its immediateenvironment and having a sensor array with at least N×M sensor elements,where N is at least 1 and M is at least 2 and an analyzer fordetermining the physical state of said analyte based upon the spatialposition of said TE and TM resonances considered together.
 17. The GMRsensor assembly defined in claim 16, wherein the input light has knownmagnitude and phase characteristics.
 18. The GMR sensor assembly definedin claim 16, wherein the N×M sensor elements configured for illuminationby a single light source input through a light shaping port.